Method for producing benzo annelated heterocycles

ABSTRACT

Process for the preparation of benzo-fused heterocycles of general formula I:                    
     in which X, R 1 , R 2 , R 3 , R 4 , R 5  and n are as defined in claim 1, by reacting tetrahydrobenzo-fused heterocycles of formula II: 
     in which X, R 1 , R 2 , R 3 , R 4 , R 5 , n and Ac are as defined in claim 1, with a catalytic amount of a noble metal catalyst in the presence of a hydrogen acceptor and then deacylating the acylated amino group by the addition of an amine.

The invention relates to a process for the preparation of benzo-fusedheterocycles of general formula I:

in which

X is S, O or NH,

R¹ is CN, NO₂, Ac, COAr, COOAr, COOH, COOA or CONR⁴R⁵,

R² and R³ independently of one another are each H, A, NO₂, CN, OH, OA orAc,

R⁴ and R⁵ independently of one another are each H, A, Ar or Ac, or

R⁴ and R⁵ together are —(CH₂)—(CH₂)_(n)—(CH₂)—,

A is alkyl having 1-6 C atoms,

Ac is acyl having 1-6 C atoms,

Ar is unsubstituted phenyl or phenyl substituted by A, NO₂, CN, OH orOA, and

n is 2, 3 or 4,

by reacting tetrahydrobenzo-fused heterocycles of formula II:

in which

X is S, O or NH,

R¹ is CN, NO₂, Ac, COAr, COOAr, COOH, COOA or CONR⁴R⁵,

R² and R³ independently of one another are each H, A, NO₂, CN, OH, OA orAc,

R⁴ and R⁵ independently of one another are each H, A, Ar or Ac, or

R⁴ and R⁵ together are —(CH₂)—(CH₂)_(n)—(CH₂)—,

A is alkyl having 1-6 C atoms,

Ac is acyl having 1-6 C atoms,

Ar is unsubstituted phenyl or phenyl substituted by A, NO₂, CN, OH orOA, and

n is 2, 3 or 4,

with a catalytic amount of a noble metal catalyst in the presence of ahydrogen acceptor and then deacylating the acylated amino group by theaddition of an amine.

Benzo-fused heterocycles of formula I are important intermediates inindustrial organic synthesis, e.g. in the manufacture of fine chemicals,dyestuffs and plant protection agents. They are also importantintermediates in the manufacture of drugs. Benzo-fused heterocycles offormula I in which X is S are particularly important in the manufactureof PDE-V inhibitors, which are known from WO 99/55708 and WO 00/78767.In particular, ethyl 2-aminobenzo[b]thiophene-3-carboxylate is anintermediate in the synthesis of4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid, which is known from WO 99/55708, or4-[4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid, which is known from WO 00/78767.

According to the classical synthesis, tetrahydrobenzo-fused compoundsare aromatized by reaction with elemental sulfur at high temperatures(literature: Gewald et al., Chem. Ber. 1968, 101, 1933). Thedisadvantages of this process are the high energy costs due to highreaction temperatures, the release of hydrogen sulfide, which is anodour nuisance, and the problems which arise in the purification,because elemental sulfur dissolves only in CS₂, which is very highlyflammable.

One particular example from the state of the art is the reaction of thecompound 2-acetylamino-3-methoxy-carbonyl-4,5-tetramethylenethiophenewith 2 equivalents of sulfur and dimethyl phthalate at temperatures ofbetween 200 and 220° C. according to G. Hallas et al., Dyes Pigm. 1997,35, 219-237. 2-Acetylamino-3-methoxy-carbonylbenzo[b]thiophene isisolated and then, in a second step, deacetylated in ethanol by reactionwith aqueous potassium hydroxide solution.

Another known possibility for aromatizing a tetrahydrobenzo-fusedcompound is to react it with an equimolar amount of a hydrogenationcatalyst. One particular example, namely the dehydrogenation of methyl2-acetylaminotetrahydrobenzothiophene-3-carboxylate with anapproximately equimolar amount of palladium on carbon (10% Pd/C) inchloroform as solvent, is described in Eiden et al., Arch. Pharm. 1984,317, 675-680.

For ecological reasons, reactions with elemental sulfur areimpracticable on the industrial scale.

In the second variant, the amount of hydrogenation catalyst used shouldbe kept as small as possible for economic reasons. Also, the benzo-fusedheterocycles formed in the dehydrogenation are often only sparinglysoluble in the solvents used and precipitate out when the heterogeneousreaction mixture cools. This makes separation of the noble metalcatalyst more difficult and considerable amounts of solvent are requiredto extract the product from the noble metal catalyst.

The object of the invention was therefore to develop a process for thepreparation of benzo-fused heterocycles of formula I which hasadvantages over the known processes of the state of the art.

Surprisingly, it was found that tetrahydrobenzo-fused compounds offormula II can be aromatized with a catalytic amount of a hydrogenationcatalyst in the presence of a hydrogen acceptor. Immediate deacylationof the amino group in the 2-position of the heterocycle by the additionof an amine provides the benzo-fused compounds of formula I as readilysoluble products, enabling the noble metal catalyst to be separated offby simple filtration. The process according to the invention is aone-pot process, i.e. the aromatization and deacylation take place insuccession without isolation of the intermediate, which in this case isthe benzo-fused heterocycle with its amino group acylated.

The meanings of all the radicals which occur several times, e.g. A orAc, are independent of one another.

The radical A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4 andparticularly preferably 1 or 2 C atoms. Alkyl is therefore especiallye.g. methyl, also ethyl, n-propyl, isopropyl, n-butyl, sec-butyl ortert-butyl, or also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl or 1,1,2- or1,2,2-trimethylpropyl. A is particularly preferably methyl or ethyl.

Ac is acyl and preferably has 1-6 C atoms. Ac is e.g. formyl, acetyl,propionyl, butyryl, pentanoyl or hexanoyl, or also trifluoroacetyl. Acis particularly preferably acetyl.

Ar is unsubstituted phenyl or phenyl substituted by A, NO₂, CN, OH orOA.

Ar is therefore preferably phenyl, o-, m- or p-methylphenyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-nitrophenyl oro-, m- or p-cyanophenyl. Ar is particularly preferably unsubstitutedphenyl.

COAr is aroyl, Ar being as defined above. COAr is particularlypreferably benzoyl.

COOAr is aryloxycarbonyl, Ar being as defined above. COOAr isparticularly preferably phenoxycarbonyl.

X is S, O or NH, S being particularly preferred.

R¹ is CN, NO₂, Ac, COAr, COOAr, COOH, COOA or CONR⁴R⁵, A, Ac and Arbeing as defined above and R⁴ and R⁵ being as defined below. R¹ isparticularly preferably CN or COOA and very particularly preferablyCOOA.

R² and R³ independently of one another are each H, A, NO₂, CN, OH, OA orAc, A and Ac being as defined above. R² and R³ are particularlypreferably H.

R⁴ and R⁵ independently of one another are each H, A, Ar or Ac, A, Arand Ac being as defined above. R⁴ and R⁵ are particularly preferably H.

R⁴ and R⁵ together are also —(CH₂)—(CH₂)_(n)—(CH₂)—, it being possiblefor n to be 2, 3 or 4. R⁴ and R⁵ together are particularly preferably—(CH₂)—(CH₂)₂—(CH₂)— or —(CH₂)—(CH₂)₃—(CH₂)— and very particularlypreferably —(CH₂)—(CH₂)₃—(CH₂)—.

The hydrogenation catalysts (or, synonymously, noble metal catalysts)used can be suitably supported noble metals such as palladium, platinumor rhodium, suitable supports being carbon, activated carbon, aluminiumoxide, barium carbonate, barium sulfate, calcium carbonate or strontiumcarbonate. The proportion of noble metal in the noble metal catalyst isbetween 1 and 20%, preferably between 5 and 10% and particularlypreferably 5%.

Palladium on activated carbon, carbon, aluminium oxide, bariumcarbonate, barium sulfate, calcium carbonate or strontium carbonate,platinum on activated carbon, carbon or aluminium oxide, or rhodium oncarbon or aluminium oxide, can be used in particular for the processaccording to the invention. It is particularly preferred to usepalladium on activated carbon (5% Pd).

Another possibility is to use noble metal salts which can be reduced insitu by a reducing agent and produce in situ a finely dividedpalladium(0) species. Examples of suitable noble metal salts arepalladium acetate, palladium bromide or palladium chloride and examplesof suitable reducing agents are hydrogen, hydrazine, sodium borohydrideor formates.

The invention further relates to a process for the preparation ofbenzo-fused heterocycles of general formula I according to claim 1 or 2,characterized in that a noble metal catalyst, selected from the groupcomprising palladium on activated carbon, carbon, aluminium oxide,barium carbonate, barium sulfate, calcium carbonate or strontiumcarbonate, platinum on activated carbon, carbon or aluminium oxide, andrhodium on carbon or aluminium oxide, is used.

Inexpensive organic hydrogen acceptors, such as the ones known to thoseskilled in the art, are particularly suitable for the process accordingto the invention, examples of inexpensive organic hydrogen acceptorsbeing styrene, α-methylstyrene, stilbene, tolans, cinnamic acid estersor cyclohexene. It is particularly preferred to use α-methylstyrene.Other hydrogen acceptors suitable for the process according to theinvention are oxygen or oxygen/gas mixtures, gas being understood asmeaning nitrogen or noble gases such as helium, neon, argon or xenon.The proportion of oxygen in the oxygen/gas mixture is between 1 and 99%,preferably between 10 and 50% and particularly preferably 15 to 25%. Theoxygen/gas mixture is particularly preferably air.

The organic hydrogen acceptor may undergo polymerization reactionsduring the aromatization. The formation of these by-products, i.e.polymers, can be reduced by adding the hydrogen acceptor in smallamounts, successively (semicontinuously) or continuously, during thereaction.

The invention further relates to a process for the preparation ofbenzo-fused heterocycles of general formula I according to one or moreof claims 1 to 3, characterized in that a hydrogen acceptor selectedfrom the group comprising styrene, α-methylstyrene, stilbene, tolans,cinnamic acid esters, for example methyl or ethyl cinnamate,cyclohexene, oxygen and oxygen/gas mixtures is used.

The dehydrogenation—and hence aromatization—using a catalytic amount ofa hydrogenation catalyst should advantageously be carried out under aninert gas atmosphere in order to avoid explosions, which is why it isadvantageous to use organic hydrogen acceptors selected from the groupcomprising styrene, α-methylstyrene, stilbene, tolans, cinnamic acidesters and cyclohexene.

To deacylate the acylated amino group of the compounds of generalformula II and of the benzo-fused intermediate after aromatization, aprimary or secondary amine boiling at between 50 and 200° C., preferablyat between 50 and 150° C., is added to the reaction mixture. It isparticularly preferred to use pyrrolidine, piperidine, piperazine,morpholine or dioctylamine and very particularly preferred to usepyrrolidine.

The invention relates to a process as described above, characterized inthat a primary or secondary amine boiling at between 50 and 200° C. isselected for the deacylation.

The aromatization and deacylation preferably take place in an inerthigh-boiling solvent, preferred inert high-boiling solvents beingbenzene, toluene, xylene, mesitylene, diphenyl ether or sulfolane.Xylene is preferably used as an isomeric mixture. The isomers o-, m- orp-xylene are also suitable. It is particularly preferred to use xylene.

The invention relates to the process described above, characterized inthat the reactions are carried out in an inert high-boiling solvent.

The dehydrogenation and deacylation preferably take place attemperatures of between 50° and 250° C., the temperature range for thedehydrogenation being preferably between 100° and 250° C. andparticularly preferably between 140° and 200° C., and the temperaturerange for the deacylation being preferably between 50° and 200° C. andparticularly preferably between 80° and 150° C.

The invention relates to the process described above, characterized inthat the reactions are carried out at temperatures of between 50 and200° C.

In the process according to the invention, the yields of benzo-fusedheterocycles of formula I are normally between 65% and 80%, includingthe deacylation step.

The process according to the invention, as described above, isparticularly suitable for the preparation of methyl or ethyl2-aminobenzo[b]thiophene-3-carboxylate. According to the invention, thisis done by reacting methyl or ethyl2-acetylaminotetrahydrobenzothiophene-3-carboxylate with a catalyticamount of a noble metal catalyst in the presence of a hydrogen acceptorand then deacetylating the acetylated amino group by the addition of anamine.

The invention further relates to the use of methyl or ethyl2-aminobenzo[b]thiophene-3-carboxylate, prepared by the processdescribed above, as an intermediate in the synthesis of4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid, which is known from WO 99/55708. Other intermediates in thesynthesis of4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid, starting from methyl 2-aminobenzo[b]thiophene-3-carboxylate, aremethyl4-(4-hydroxybenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylate,methyl4-(4-chlorobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylateand methyl4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylate.

The process known from WO 99/55708 for the preparation of4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid comprises the following steps:

Step a) methyl 2-aminotetrahydrobenzothiophene-3-carboxylate is firstcyclized with methyl 4-cyanocyclohexanecarboxylate;

Step b) the tetrahydrobenzothiophene unit of the intermediate formed isdehydrogenated with sulfur to give the compound methyl4-(4-hydroxybenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylate;

Step c) the hydroxyl group is chlorinated by reaction with achlorinating agent, preferably POCl₃;

Step d) the compound methyl4-(4-chlorobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylatefrom step c) is reacted with 3-chloro-4-methoxybenzylamine to give theester methyl4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylate;

Step e) the ester from step d) is saponified; and

Step f) the free acid is converted to a pharmacologically acceptablesalt.

For ecological reasons, however, reaction with elemental sulfur isimpracticable on the industrial scale.

The invention therefore relates to a process for the preparation of4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid or one of the pharmaceutically acceptable salts, characterized inthat it comprises the following steps:

Step a) alkyl 2-acetylaminotetrahydrobenzothiophene-3-carboxylate isreacted according to one or more of claims 1 to 7 with a catalyticamount of a noble metal catalyst in the presence of a hydrogen acceptor,and the acetylated amino group is then deacetylated by the addition ofan amine to give the compound alkyl2-aminobenzo[b]thiophene-3-carboxylate;

Step b) the alkyl 2-aminobenzo[b]thiophene-3-carboxylate is cyclized byreaction with alkyl 4-cyanocyclohexanecarboxylate;

Step c) the hydroxyl group of the compound alkyl4-(4-hydroxybenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylatefrom step b) is chlorinated with a chlorinating agent;

Step d) the compound alkyl4-(4-chlorobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylatefrom step c) is reacted with 3-chloro-4-methoxybenzylamine to give theester alkyl4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylate;

Step e) the ester from step d) is saponified; and

Step f) the free acid is converted to a pharmacologically acceptablesalt.

The alkyl ester is for example the methyl, ethyl, propyl or butyl ester.It is preferred to use methyl or ethyl2-acetylaminotetrahydrobenzothiophene-3-carboxylate as the alkyl2-acetylaminotetrahydrobenzothiophenecarboxylate and all the subsequentintermediates based on this ester unit. It is preferred to use methyltrans-4-cyanocyclohexanecarboxylate as the alkyl4-cyanocyclohexanecarboxylate and all the subsequent intermediates basedon this ester unit.

The reaction conditions of the cyclization b) in the preparationaccording to the invention of4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid are known from Eur. J. Med. Chem. 1988, 23, 453.

Examples of suitable chlorinating agents are POCl₃, SOCl₂ or cyanuricchloride. Chlorination with POCl₃ or SOCl₂ takes place under reactionconditions known to those skilled in the art. The reaction preferablytakes place in an inert solvent, for example in toluene, methylenechloride or dimethylformamide.

The reactions of methyl4-(4-chlorobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylatein steps d) and e) of the process according to the invention for thepreparation of4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid, as described above, and step f) are known from WO 99/55708,Example 1, pp. 11-12, and Example 2, p. 14.

The invention further relates to the use of methyl or ethyl2-aminobenzo[b]thiophene-3-carboxylate, prepared by the processdescribed above, as an intermediate in the synthesis of4-[4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid, which is known from WO 00/78767. Other intermediates in thesynthesis of4-[4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid, starting from methyl 2-aminobenzo[b]thiophene-3-carboxylate, aremethyl4-(4-hydroxybenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylate,methyl4-(4-chlorobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylateand methyl4-[4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylate.

In the process known from WO 00/78767 for the preparation of4-[4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid, methyl4-(4-chlorobenzothieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylate isreacted with 3-chloro-4-hydroxybenzylamine, the methyl4-(4-chloro-benzothieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylatebeing prepared, as also described in WO 99/55708, by the cyclization ofmethyl 2-amino-5,6,7,8-tetrahydrobenzothiophene-3-carboxylate withmethyl 3-cyanocyclohexanecarboxylate, dehydrogenation with sulfur andsubsequent chlorination with phosphorus oxychloride/dimethylamine.

For ecological reasons, however, reaction with elemental sulfur isimpracticable on the industrial scale.

The invention therefore relates to a process for the preparation of4-[4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid or one of the pharmaceutically acceptable salts, characterized inthat it comprises the following steps:

Step a) alkyl 2-acetylaminotetrahydrobenzothiophene-3-carboxylate isreacted according to one or more of claims 1 to 7 with a catalyticamount of a noble metal catalyst in the presence of a hydrogen acceptor,and the acetylated amino group is then deacetylated by the addition ofan amine to give the compound alkyl2-aminobenzo[b]thiophene-3-carboxylate;

Step b) the alkyl 2-aminobenzo[b]thiophene-3-carboxylate is cyclized byreaction with alkyl 4-cyanocyclohexanecarboxylate;

Step c) the hydroxyl group of the compound alkyl4-(4-hydroxybenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylatefrom step b) is chlorinated with a chlorinating agent;

Step d) the compound alkyl4-(4-chlorobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylatefrom step c) is reacted with 3-chloro-4-hydroxybenzylamine to give theester alkyl4-[4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylate;

Step e) the ester from step d) is saponified; and

Step f) the free acid is converted to a pharmacologically acceptablesalt.

The definitions of the term alkyl ester and the reaction conditions ofthe cyclization and chlorination, as described above for4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid, also apply to the compound4-[4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid. The reaction conditions of steps d) to f) are known from WO99/55708, Examples 1 and 2, and from WO 00/78767, Examples 1 and 7.

In the following examples and also in the above explanations, thetemperatures are given in °C. In the examples, “conventional work-up”has the following meaning: water is added if necessary, the pH isadjusted to between 2 and 10 if necessary, depending on the constitutionof the end product, extraction is carried out with ethyl acetate ordichloromethane and the organic phase is separated off, dried oversodium sulfate, evaporated and purified by chromatography on silica geland/or by crystallization.

EXAMPLE 1

A suspension of 22.9 g of palladium on activated carbon (5% Pd/C)(Degussa-Hüls; E 101 Rw 5%, 53.9% moisture content) in 260 ml of xyleneis refluxed in a water separator until no more water separates off. Asolution of 49.7 g of N-acetylthiophenenitrile in 210 ml of xylene isadded to this reaction mixture at room temperature and the reactionmixture is heated to 143° C. 48 g of α-methylstyrene are added after 2 hand a further 25 g of α-methylstyrene are added after 96 h. Deacylationis started by the addition of 47 g of pyrrolidine after a reaction timeof 127 h, the temperature being kept at 137° C. After a reaction time of48 h, the mixture is filtered hot and the residue is rinsed with 100 mlof ethyl acetate and 200 ml of 10% HCl solution. The organic phase iswashed with distilled water until the pH of the washings is 4. Theorganic solvent is distilled off to give2-aminobenzo[b]thiophene-3-carbonitrile in a yield of 81%.

EXAMPLE 2

2 g of palladium catalyst (5% Pd/C, approx. 50% moisture content;Degussa-Hüls; E 101 RW 5%) are added to a solution of 10 g of ethyl2-acetylaminotetrahydrobenzothiophenecarboxylate in 80 ml of mesityleneand the mixture is heated to 170° under nitrogen. 2 g of ethyl cinnamateare metered in over 30 min and stirring is continued for 21 h. Thetemperature is then lowered to 100° and 10 ml of pyrrolidine are added.The reaction mixture is stirred for 25 h under nitrogen. The catalyst isthen filtered off and rinsed with 60 g of ethanol. The solutions arecombined and the solvent is distilled off. The residue is taken up inethyl acetate and washed twice with 1 N HCl and once with water. Afterdistillation of the solvent and subsequent crystallization from2-propanol, ethyl 2-aminobenzo[b]thiophene-3-carboxylate is obtainedwith a yield of 64%.

EXAMPLE 3

14.4 g of hydrogenation catalyst (Degussa-Hüls; E 101 R/W 5%) are addedto a solution of 36 g of ethyl2-acetylaminotetrahydrobenzothiophene-3-carboxylate in 250 ml of xylene(isomeric mixture) and the mixture is heated to a constant temperatureof 139° C. to 141° C. 47 g of α-methylstyrene are metered in over aperiod of 5 h. The mixture is then refluxed for a further 36 h. It iscooled to 102° C., 32 g of pyrrolidine are added and the mixture isbrought back to the reflux point (127° C.); it is stirred for 20 h atthis temperature. After cooling to 20° C., the Pd/carbon is filteredoff, the filtrate is concentrated to a residue, and the residue is takenup in 75 ml of ethyl acetate and washed with three times 12 ml of 10%hydrochloric acid. The organic phase is washed with twice 5 ml of waterand then concentrated to a residue. This is recrystallized from 50 ml ofisopropanol to give 21 g of ethyl 2-aminobenzothiophene-3-carboxylate inthe form of slightly yellowish crystals (70.5% yield).

The other synthetic steps are known from Eur. J. Med. Chem. 1988, 23,453 and WO 99/55708, Example 1, pp. 11-12, and Example 2, p. 14.

What is claimed is:
 1. Process for the preparation of benzo-fusedheterocycles of general formula I:

in which X is S, O or NH, R¹ is CN, NO₂, Ac, COAr, COOAr, COOH, COOA orCONR⁴R⁵, R² and R³ independently of one another are each H, A, NO₂, CN,OH, OA or Ac, R⁴ and R⁵ independently of one another are each H, A, Aror Ac, or R⁴ and R⁵ together are —(CH₂)—(CH₂)_(n)—(CH₂)—, A is alkylhaving 1-6 C atoms, Ac is acyl having 1-6 C atoms, Ar is unsubstitutedphenyl or phenyl substituted by A, NO₂, CN, OH or OA, and n is 2, 3 or4, by reacting tetrahydrobenzo-fused heterocycles of formula II:

in which X is S, O or NH, R¹ is CN, NO₂, Ac, COAr, COOAr, COOH, COOA orCONR⁴R⁵, R² and R³ independently of one another are each H, A, NO₂, CN,OH, OA or Ac, R⁴ and R⁵ independently of one another are each H, A, Aror Ac, or R⁴ and R⁵ together are —(CH₂)—(CH₂)—(CH₂)—, A is alkyl having1-6 C atoms, Ac is acyl having 1-6 C atoms, Ar is unsubstituted phenylor phenyl substituted by A, NO₂, CN, OH or OA, and n is 2, 3 or 4, witha catalytic amount of a noble metal catalyst in the presence of ahydrogen acceptor and then deacylating the acylated amino group by theaddition of an amine.
 2. Process according to claim 1 for thepreparation of methyl or ethyl 2-aminobenzo[b]thiophene-3-carboxylate.3. Process according to claim 1, wherein the noble metal catalystcomprises palladium on activated carbon, carbon, aluminium oxide, bariumcarbonate, barium sulfate, calcium carbonate or strontium carbonate,platinum on activated carbon, carbon or aluminium oxide, or rhodium oncarbon or aluminium oxide.
 4. Process according to claim 1, wherein thehydrogen acceptor comprises styrene, α-methylstyrene, stilbene, atolans, a cinnamic acid esters, cyclohexene, oxygen or an oxygen/gasmixture.
 5. Process according to claim 1, wherein the amine comprises aprimary or secondary amine boiling at 50-200° C.
 6. Process according toclaim 1, wherein the reactions are carried out at a temperature of50-200° C.
 7. Process according to claim 1, wherein the reactions arecarried out in a high-boiling solvent.
 8. A process for synthesizing4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid, comprising reacting an intermediate comprising methyl or ethyl2-aminobenzo[b]thiophene-3-carboxylate with methyl4-cyanocyclohexanecarboxylate.
 9. Process for the preparation of4-[4-(3-chloro-4-methoxybenzylamino)benzo [4,5]thieno[2,3-d]-pyrimidin-2-yl]cyclohexanecarboxylic acid or one of thepharmaceutically acceptable salts, comprising: a) reacting alkyl2-acetylaminotetrahydrobenzo-thiophene-3-carboxylate according to claim1 with a catalytic amount of a noble metal catalyst in the presence of ahydrogen acceptor, and then deacetylating the acetylated amino group bythe addition of an amine to give the compound an alkyl2-aminobenzo-[b]thiophene-3-carboxylate; b) cyclizing the alkyl2-aminobenzo[b]thiophene-3-carboxylate by reaction with alkyl4-cyanocyclohexanecarboxylate; c) chlorinating the hydroxyl group of thecompound alkyl4-(4-hydroxybenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylatefrom b) with a chlorinating agent; d) reacting the compound alkyl4-(4-chlorobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylatefrom c) with 3-chloro-4-methoxybenzylamine to give the ester alkyl4-[4-(3-chloro-4-methoxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexane-carboxylate;e) saponifying the ester from d); and f) converting the free acid to apharmacologically acceptable salt.
 10. A process for synthesizing4-4-(3-chloro-4-hydroxybenzylamino)benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylicacid, comprising reacting an intermediate comprising methyl or ethyl2-aminobenzo[b]thiophene-3-carboxylate with methyl3-cyano-cyclohexanecarboxylate.
 11. Process for the preparation of4-[4-(3-chloro-4-hydroxybenzylamino)benzo [4,5]thieno[2,3-d]-pyrimidin-2-yl]cyclohexanecarboxylic acid or one of thepharmaceutically acceptable salts, comprising: a) reacting alkyl2-acetylaminotetrahydrobenzo-thiophene-3-carboxylate according to claim1 with a catalytic amount of a noble metal catalyst in the presence of ahydrogen acceptor, and then deacetylating the acetylated amino group bythe addition of an amine to give the compound alkyl2-aminobenzo-[b]thiophene-3-carboxylate; b) cyclizing the alkyl2-aminobenzo[b]thiophene-3-carboxylate by reaction with alkyl4-cyanocyclohexanecarboxylate; c) chlorinating the hydroxyl group of thecompound alkyl4-(4-hydroxybezo[4,5]thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylatefrom b) with a chlorinating agent; d) reacting the compound alkyl4-(4-chlorobenzo[4,5]-thieno[2,3-d]pyrimidin-2-yl)cyclohexanecarboxylatefrom c) with 3-chloro-4-hydroxybenzylamine to give the ester alkyl4-[4-(3-chloro-4-hydroxybenzylamino)benzo-[4,5]thieno[2,3-d]pyrimidin-2-yl]cyclohexanecarboxylate;e) saponifying the ester from d); and f) converting the free acid to apharmacologically acceptable salt.
 12. A process according to claim 1,wherein A is methyl or ethyl.
 13. A process according to claim 1,wherein Ac is acetyl.
 14. A process according to claim 1, wherein Ar isunsubstituted phenyl.
 15. A process according to claim 1, wherein R¹ isCOOA.
 16. A process according to claim 1, wherein R²-R⁵ are H.